WO2014020611A1 - Procédé et système pour la surveillance non invasive de paramètres biologiques ou biochimiques d'un individu - Google Patents

Procédé et système pour la surveillance non invasive de paramètres biologiques ou biochimiques d'un individu Download PDF

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Publication number
WO2014020611A1
WO2014020611A1 PCT/IL2013/050658 IL2013050658W WO2014020611A1 WO 2014020611 A1 WO2014020611 A1 WO 2014020611A1 IL 2013050658 W IL2013050658 W IL 2013050658W WO 2014020611 A1 WO2014020611 A1 WO 2014020611A1
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Prior art keywords
correlation function
peak
time
blood
parameter
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PCT/IL2013/050658
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English (en)
Inventor
Zeev Zalevsky
Javier Garcia
Yevgeny Beiderman
Israel MARGALIT
Nisim Nisan OZANA
Nadav ARBEL
Vicente MICO
Martin SANZ SABATER
Original Assignee
Bar Ilan University
Universitat De Valencia
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Priority claimed from US13/564,381 external-priority patent/US9668672B2/en
Application filed by Bar Ilan University, Universitat De Valencia filed Critical Bar Ilan University
Priority to EP13753907.8A priority Critical patent/EP2879568A1/fr
Priority to CN201380041088.5A priority patent/CN104736042B/zh
Priority to JP2015524904A priority patent/JP6645828B2/ja
Priority to CA2879255A priority patent/CA2879255C/fr
Priority to US14/168,730 priority patent/US9636041B2/en
Publication of WO2014020611A1 publication Critical patent/WO2014020611A1/fr
Priority to IL236742A priority patent/IL236742B/en
Priority to HK15111056.1A priority patent/HK1210001A1/xx
Priority to US15/483,828 priority patent/US10398314B2/en

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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/0205—Simultaneously evaluating both cardiovascular conditions and different types of body conditions, e.g. heart and respiratory condition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61B3/00—Apparatus for testing the eyes; Instruments for examining the eyes
    • A61B3/0008—Apparatus for testing the eyes; Instruments for examining the eyes provided with illuminating means
    • A—HUMAN NECESSITIES
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    • A61B3/10—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions
    • A61B3/102—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for optical coherence tomography [OCT]
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    • A61B3/10—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions
    • A61B3/16—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for measuring intraocular pressure, e.g. tonometers
    • A61B3/165—Non-contacting tonometers
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    • A61B5/02028—Determining haemodynamic parameters not otherwise provided for, e.g. cardiac contractility or left ventricular ejection fraction
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    • A61B5/0205—Simultaneously evaluating both cardiovascular conditions and different types of body conditions, e.g. heart and respiratory condition
    • A61B5/02055—Simultaneously evaluating both cardiovascular condition and temperature
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    • A61B5/021—Measuring pressure in heart or blood vessels
    • A61B5/02108—Measuring pressure in heart or blood vessels from analysis of pulse wave characteristics
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    • A61B5/021—Measuring pressure in heart or blood vessels
    • A61B5/02108—Measuring pressure in heart or blood vessels from analysis of pulse wave characteristics
    • A61B5/02116—Measuring pressure in heart or blood vessels from analysis of pulse wave characteristics of pulse wave amplitude
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    • A61B5/024—Detecting, measuring or recording pulse rate or heart rate
    • A61B5/02416—Detecting, measuring or recording pulse rate or heart rate using photoplethysmograph signals, e.g. generated by infrared radiation
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    • A61B5/026—Measuring blood flow
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    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
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    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
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    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A—HUMAN NECESSITIES
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    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7271—Specific aspects of physiological measurement analysis
    • A61B5/7275—Determining trends in physiological measurement data; Predicting development of a medical condition based on physiological measurements, e.g. determining a risk factor
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    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/02028—Determining haemodynamic parameters not otherwise provided for, e.g. cardiac contractility or left ventricular ejection fraction
    • A61B5/02035—Determining blood viscosity
    • A—HUMAN NECESSITIES
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    • A61B5/14542—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring blood gases
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    • A61B5/45—For evaluating or diagnosing the musculoskeletal system or teeth
    • A61B5/4504—Bones

Definitions

  • This invention relates to a method and system for non-invasively monitoring biological or biochemical parameters and conditions of an individual.
  • the present invention is particularly useful for monitoring various parameters and conditions relating to biological fluids such as blood, e.g. glucose concentration in blood, breathing, blood oxymetry, blood coagulation, as well as for monitoring parameters related to an internal organ being inspected.
  • the human body contains many fluids having vital functions within the body. For example, blood flowing in the circulatory system delivers necessary substances such as nutrients and oxygen to cells, and transports metabolic waste products away from those cells.
  • Another fluid is the aqueous humor in the eyes.
  • the aqueous humor maintains the intraocular pressure and inflates the globe of the eye, provides nutrition (e.g. amino acids and glucose) for the avascular ocular tissues, posterior cornea, trabecular meshwork, lens, and anterior vitreous.
  • blood glucose level also referred to as blood glucose concentration
  • blood oxygen level is typically monitored to identify oxygen saturation condition that enables identification of hypoxemia as well allows estimation of hemoglobin in blood.
  • Blood alcohol level is indicative of alcohol consumption and may be used to determine detrimental effects of alcohol on the gastrointestinal, cardiovascular and central nervous systems. Blood alcohol level is also indicative of impairment in a person's judgment and his ability to perform certain actions, such as driving a vehicle.
  • intraocular pressure In the eye, an important property of the aqueous humor is its pressure. This property is commonly called “intraocular pressure”. A high intraocular pressure may be indicative of disorders in the eye, such as glaucoma, ulceris, and retinal detachment.
  • glucose meters In the field of measuring blood-related parameters, such as glucose level and oxygen saturation, many non-invasive techniques have been devised, including impedance-based techniques and optical. For example, in glucose meters based on near infrared spectroscopy, a tissue is illuminated with light in the infrared spectrum, and the light reflected by the tissue and/or the light transmitted through the tissue is measured. The portion of light that is reflected and/or transmitted is indicative of the blood glucose level. Such glucose meters are used for tissue investigation in different depths varying from 1 to 100 millimeters or 10 to 50 micrometers. Some glucose meters use Raman spectroscopy to measure scattered light that has been influenced by the oscillation and rotation caused by glucose.
  • Glucose meters based on photo-acoustic spectroscopy measure parameters of an acoustic pressure wave created by rapid heating of the sampled area. Other glucose meters measure changes in the scattering and the polarization parameters of light caused by glucose.
  • Femtosecond pulse interferometry can be used to determine glucose concentration, by measuring the group refraction index of a glucose solution using a time delay of femtosecond order in a time-of-flight method.
  • Optical coherence tomography can be used to measure and analyze the interference pattern between the coherently backscattered light from specific layers of tissues and a reference beam.
  • alcohol level is usually examined by determining blood alcohol concentration (BAC) in breath and blood of the affected person.
  • BAC blood alcohol concentration
  • the principle of BAC measurement is based on the fact that alcohol, taken orally, goes into the body system. Equilibrium distribution of alcohol into the different parts of the body mainly liver, kidney, brain, and lungs is attained very rapidly.
  • the ratio of alcohol in the blood to alcohol in alveolar air is approximately 2,100: 1 at 34°C, the temperature at which the breath leaves the mouth.
  • Goldmann tonometry mainly suffers from inter-individual variations due to difference in corneal thickness and rigidity while being an invasive (contact) technique with limitations for monitoring the IOP over time.
  • this standard method which involves touching the cornea, also consequently necessitates the use of anesthetic eye drops.
  • the present invention aims at providing a novel technique for non-invasively and contactless monitoring one or more parameters/conditions of a subject by analyzing image data corresponding to defocused images of secondary speckle pattern responses of the subject varying over time in response to coherent illumination. More specifically, the invention is used for monitoring/measuring parameters/properties of bodily fluids, such as blood, aqueous humor, cerebrospinal fluid in the cranium, and is therefore described below with respect to this specific medical application.
  • bodily fluids such as blood, aqueous humor, cerebrospinal fluid in the cranium
  • an endoscope-based system for monitoring one or more biomedical parameters/conditions of (or related to) an internal organ by analyzing image data corresponding to defocused images of secondary speckle pattern generated at a surface of the internal organ.
  • the present disclosure may be used for monitoring (measuring) one or more parameters (properties) of fluid streams within organs as well as for detecting different types of infections, e.g. retinal diseases, cancer cells and etc.
  • infections e.g. retinal diseases, cancer cells and etc.
  • organ may also be contemplated as a portion of an organ in the following description.
  • an organ in the meaning of the present disclosure may refer to a blood vessel or to a tumor cell within an organ.
  • organ may refer generally to an organ/tissue in a subject's body i.e. accessible by invasive techniques involving incision of the skin or by non-invasive techniques which do not involve incision of the skin such as endoscopy or puncture, etc.
  • the present invention makes use of the imaging technique disclosed in PCT Patent Publication WO2009/013738 developed by co-inventors of the present application and assigned to the assignee of the present application.
  • This technique is aimed at determining a motion of an object by an optical system, a so-called "optophone".
  • an imaging system focused on a plane displaced from the object.
  • the inventors have now identified that various biological or biochemical conditions of a subject's body affect a motion of the respective body portion.
  • the glucose level and alcohol level in blood affect, inter alia, the viscosity of blood.
  • a change in the blood's viscosity affects the friction between the blood fluid and the vessel walls, and therefore produces a unique vibration profile in the blood vessel and on the skin proximal to the blood vessel.
  • some of the above mentioned chemicals, such as alcohol affect the rate and shape of the heart pulsation which can be extracted using the proposed optical technique.
  • the present invention is thus based on the understanding that there is a defined relation between a motion of the body portion (resulting from a motion of a bodily fluid in said portion) and one or more properties of the fluid.
  • the inventors have therefore developed a novel technique that utilizes relations between various parameters, characterizing a change in detected speckle pattern from the body over time, and the body conditions.
  • the present invention generally provides an optical technique for monitoring/measuring various parameters/conditions of a subject (an individual) that affect an optical response of a region of interest in the subject's body to incident light due to motion effects in said region of interest.
  • the motion effects can be determined by analyzing the optical response being in the form of a sequence of speckle patterns returned from a portion of the subject's body in response to illumination thereof by coherent light according to a certain sampling time pattern.
  • speckle pattern is detected over time with a certain sampling rate, and variations of the speckle pattern images are determined. More specifically, a spatial correlation function between successively sampled frames (images) is determined.
  • the correlation function typically has a Gaussian-like spatial profile and can therefore be described by a "correlation peak" whose temporal variations correspond to a change in the speckle pattern over time. This may be a change in a position (shift) of the speckle pattern in the detector plane causing the change in the spatial position of the correlation peak (the shift of the speckle pattern in time shifts also the obtained spatial correlation peak), and/or a change in the shape or distribution of the speckle pattern causing the change in the correlation peak value.
  • the change in location and/or value of the peak of the spatial correlation function over time is analyzed in accordance with the condition/property to be determined.
  • the invention utilizes predetermined models, each model presenting a relation between one or more parameters of the time varying spatial correlation function (e.g. the time varying position of the spatial correlation peak or the time varying value of this peak) and a biological or biochemical property/condition of the body.
  • appropriate one or more parameters of the temporal change in some features of the spatial correlation function are determined and then the selected model is applied to determine biological or biochemical property/condition.
  • the selected model is applied to determine biological or biochemical property/condition.
  • the inventors have found that human blood vessels vibrate due to variable (from systolic to diastolic) blood pressure.
  • the human wrist may be one possible spot for blood vessels observation and vibration analysis, especially for heart beat monitoring.
  • blood pulse pressure the difference between the systolic and diastolic pressures
  • blood flow volume the relative
  • pulse wave velocity the pulse wave velocity
  • substance concentration in blood etc.
  • a vibration profile of a blood vessel is a unique one. It is characterized by many individual properties, such as vessel elasticity, human fat layer, blood viscosity etc. Therefore any change of one of these properties can distort this profile.
  • the glucose level and alcohol level in blood affect, inter alia, the viscosity of blood.
  • a change in the blood's viscosity affects the friction between the blood fluid and the vessel walls, and therefore produces a unique vibration profile in the blood vessel and on the skin proximal to the blood vessel.
  • some of the above mentioned chemicals, such as alcohol affect the rate and shape of the heart pulsation, which can extracted using the proposed optical technique.
  • an optical technique to monitor substance concentration/level in blood based on determining and analyzing a change in the speckle pattern over time caused by skin vibrations due to blood flux pulsation.
  • the secondary speckle pattern's spatial correlation function is indicative of the motion of a region of human skin (e.g. skin on the wrist) illuminated by a spot of laser beam, and can be therefore used to determine the substance concentration/level in blood.
  • One or more properties of the blood can be extracted by determining parameters in the time varying characteristics of features in the spatial correlation function of the speckle pattern (features as the position of the correlation peak or its value) generated in response to coherent illumination of the skin portion.
  • the inventors have shown that at least one parameter of the temporal change in the spatial correlation function is in good agreement with the blood glucose level estimated by a conventional measurement technique. Also, the inventors have shown that parameter(s) of the temporal change in the spatial correlation function is in good agreement with blood alcohol level measured by a conventional technique.
  • intraocular pressure affects the vibration of the eye (e.g. sclera, iris, eye lid), and that a relation exists between intraocular pressure and some parameters of the temporal change in the spatial correlation function of a secondary speckle pattern generated in response to coherent illumination of the eye (the temporal change in the spatial correlation function being indicative of the eye's vibration over time). Therefore, according to some embodiments of the present invention, there is provided a technique for measuring intraocular pressure based on detection and analysis of the temporal change in the spatial correlation function.
  • beams of several wavelengths may be used to (simultaneously or successively) illuminate the region of interest, and the secondary speckle pattern (and the corresponding time varying spatial correlation function) is determined for each wavelength separately.
  • the time varying spatial correlation function is determined for each wavelength, and a relation between these two or more functions is determined, or a relation (e.g. ratio) between selected parameters of the different time varying spatial correlation functions is determined, as the case may be. More specifically, the time varying spatial correlation function for each wavelength is used (e.g.
  • the so-obtained time varying ratio is utilized to define the parameter of interest (e.g. the width of peaks, the standard deviation of background noise, etc.), for determination of the blood parameter using one or more appropriate models.
  • the parameter of interest e.g. the width of peaks, the standard deviation of background noise, etc.
  • This can be useful, for example, in the estimation of blood oxygen level which today is done by pulse oxymetry based on determination of the ratio of transmission of the blood in two predefined wavelengths.
  • a system for use in monitoring one or more conditions of a subject's body includes a control unit, which includes an input port, a memory utility, and a processor utility.
  • the input port is configured for receiving image data in the form of a sequence of speckle patterns generated by a portion of the subject's body according to a certain sampling time pattern.
  • the memory utility is configured for storing one or more predetermined models, the model comprising data indicative of a relation between one or more measurable parameters and one or more conditions of the subject's body.
  • the processor utility configured and operable for carrying out the following: processing the image data and determining a spatial correlation function between successive speckle patterns in the sequence, and determining a time varying spatial correlation function in the form of a time-varying function of at least one feature of the correlation function, the time- varying spatial correlation function being indicative of a change of the speckle pattern over time; selecting at least one parameter of the time-varying spatial correlation function, and applying to said at least one parameter one or more of the models to determine one or more corresponding body conditions; and generating output data indicative of said one or more corresponding body conditions.
  • the at least one feature of the correlation function comprises at least one of the following: a position of a peak of the correlation unit, and a value of a peak of the correlation function.
  • said one or more body conditions to be monitored comprises blood glucose concentration.
  • the at least one parameter of the time varying function may comprise at least one of the following: positive pulse amplitude, and ratio between positive and negative peak amplitudes.
  • said one or more body conditions to be monitored comprises blood alcohol concentration.
  • the at least one parameter of the time varying function may comprise at least one of the following: pulse size, positive pulse size, distance between peak polarities, ratio between main and secondary peak positions, ratio between main and secondary peak amplitudes, and standard deviation of background noise.
  • said one or more body conditions to be monitored comprise intra optical pressure (IOP).
  • IOP intra optical pressure
  • the at least one parameter of the time varying function comprises an amplitude of oscillation.
  • the body condition is blood pulse pressure.
  • the at least one parameter of the time varying spatial correlation function comprises the amplitude of the main peak (pulse amplitude).
  • a system for use in monitoring one or more conditions of a subject's body includes an imaging device and a control unit.
  • the imaging device is configured for imaging a predetermined portion of the subject's body, the imaging device comprising a coherent light source for illuminating said portion of the subject's body with a predetermined number of wavelengths according to a certain sampling time pattern, and a pixel detector array configured and operable for detecting secondary speckle pattern generated by the illuminated portion of the body and generating measured image data indicative of the detected secondary speckle pattern.
  • the control unit is configured and operable for receiving and analyzing said measured image data, the control unit comprising: a memory utility for storing one or more predetermined models, the model comprising data indicative of a relation between one or more measurable parameter and one or more conditions of the subject's body; and a processor utility configured and operable for: processing the image data and determining a spatial correlation function between successive speckle patterns in the sequence, and determining a time varying spatial correlation function in the form of a time-varying function of at least one feature of the correlation function, the time- varying spatial correlation function being indicative of a change of the speckle pattern over time; selecting at least one parameter of the time-varying spatial correlation function, and applying to said at least one parameter one or more of the models to determine one or more corresponding body conditions; and generating output data indicative of said one or more corresponding body conditions.
  • a method for use in monitoring one or more conditions of a subject's body comprising: providing image data measured by a pixel detector array and being in the form of a sequence of speckle patterns generated by a portion of the subject's body in response to illumination thereof by coherent light according to a certain sampling time pattern; providing one or more predetermined models, the model comprising data indicative of a relation between one or more measurable parameters and one or more conditions of the subject's body; processing the image data and determining a spatial correlation function between successive speckle patterns in the sequence, and determining a time-varying spatial correlation function in the form of a time-varying function of at least one feature of the correlation function, the time- varying spatial correlation function being indicative of a change of the speckle pattern over time; analyzing the time- varying spatial correlation function and selecting at least one parameter of the time-varying function in accordance with one or more body conditions to be determined; and analyzing said at least one selected parameter using one or more of the
  • said one or more conditions of a subject's body are associated with one or more properties of at least one bodily fluid.
  • said at least bodily fluid comprises at least one of blood and aqueous humor.
  • the at least one feature of the correlation function may comprise at least one of the following: a position of a peak of the correlation unit, and a value of a peak of the correlation function.
  • said one or more body conditions to be monitored comprises blood glucose concentration.
  • the at least one parameter of the time varying function may comprise at least one of the following: positive pulse amplitude, and ratio between positive and negative peak amplitudes.
  • the at least one parameter of the time varying function may comprise at least one of the following: pulse amplitude, positive pulse size, distance between peak polarities, ratio between main and secondary peak positions, ratio between main and secondary peak amplitudes, and standard deviation of background noise.
  • said one or more body conditions to be monitored comprise intra optical pressure (IOP).
  • IOP intra optical pressure
  • the body condition is blood pulse pressure.
  • the at least one parameter of the time varying spatial correlation function comprises the amplitude of the main peak (pulse amplitude).
  • the invention can be used together with a conventional imaging system such as endoscope of any suitable configuration for inspecting/measuring internal organs of a subject.
  • Endoscopes are the common medical instrumentation to perform medical inspection of internal organs. There are two main types of endoscopes: flexible and rigid.
  • the flexible endoscopes are being constructed out of a bundle of single mode fibers while each fiber in the bundle transmits backwards spatial information corresponding to a single spatial point, i.e. a single pixel.
  • the fibers bundle may go into the body while the imaging camera is located outside.
  • Interface optics adapts the photonic information coming out of the bundle to the detection camera.
  • the reason for using single mode fiber for each fiber in the bundle rather than multi mode fibers (capable of transmitting spatial information that is corresponding to plurality of pixels) is related to the fact that when inserting the endoscope and while navigating it inside the body it may be bent. When multi mode fibers are bent the spatial modes are coupled to each other and the image is strongly distorted.
  • the typical diameter of a single mode fiber in the bundle is about 30 ⁇ (this is the diameter of its cladding, the core has diameter of about 8-9 ⁇ ).
  • the typical number of fibers in the bundle is about 10,000- 30,000.
  • Typical overall diameter (of the entire bundle) is about 3mm-5mm.
  • an endoscope utilizing a multicore fiber is described in US Patent Pubication US 2010/0046897 which discloses an endoscope system including an image fiber with an image fiber main body made of a plurality of cores for forming pixels and a cladding common thereto; and an optical system connected to an eyepiece side of the image fiber for causing laser light to enter the image fiber and for taking in an image from the image fiber, in which the image fiber has the cores arranged substantially uniformly over a cross-section of the image fiber main body, the cross-section being perpendicular to a longitudinal direction of the image fiber main body.
  • a monitoring system for use inspecting an internal organ, the system comprising an imaging device for imaging a predetermined portion of the subject's body, and a control unit.
  • the imaging device comprises a coherent light source for illuminating said portion of the subject's body with a predetermined number of wavelengths according to a certain sampling time pattern, and a pixel detector array configured and operable for detecting secondary speckle pattern generated by the illuminated portion of the body and generating measured image data indicative of the detected secondary speckle pattern.
  • the imaging device may have any suitable known configuration.
  • the imaging device comprises a multicore fiber configured for transferring light between a proximal end and a distal end of the multicore fiber which is intended to be placed in proximity of the internal organ.
  • the control unit is configured and operable as described above for receiving and analyzing the measured image data, using one or more predetermined models comprising data indicative of a relation between one or more measurable parameter and one or more conditions of the subject's body, to determine a spatial correlation function between successive speckle patterns in the sequence.
  • Fig. 1A is a block diagram of a system of the present invention for monitoring a subject's condition by measuring one or more biological or biochemical parameters/conditions of the subject;
  • Fig. IB is a schematic illustration of the system of the invention used together with an imaging system for measuring a motion of a portion of the subject's body;
  • Figs. 2A-2B are schematic drawings illustrating the principles of the technique for measuring motion of an object used in the measurement unit of the system of Fig. lA or IB;
  • Figs. 3A-3C exemplify the processing of measured data by the control unit of the system of Fig. 1A or IB;
  • Fig. 4 exemplifies the use of the system of the invention with an endoscope, and shows a specific but not limiting example of the configuration of a light guiding unit suitable to be used in the endoscospe;
  • Fig. 5 is a flowchart exemplifying a method of the present invention for monitoring a subject's condition by measuring one or more biological or biochemical properties of the subject;
  • Fig. 6A is a graph exemplifying a function indicative of a time variation of the speckle pattern, as generated by the system of the present invention, and illustrating a plurality of parameters of the function in the time domain that can be used for determining the body conditions;
  • Fig. 6B is a graph which illustrates a test on a subject, in which a substantially constant level of blood glucose concentration was shown to correspond to a substantially constant negative pulse width (parameter 6 of Fig. 6A);
  • Figs. 6C-6F are graphs illustrating the change in a test subject's blood glucose level and the corresponding change in the amplitude of positive peak (parameter 1 of Fig. 6A);
  • Figs. 7A-7D are graphs illustrating the change in a test subject's blood glucose level and the corresponding change in the ratio between positive and negative peak (parameter 9 of Fig. 6A);
  • Figs. 8A-8D are graphs illustrating the change in a second test subject's blood glucose level and the corresponding change in the amplitude of positive peak (parameter 1 of Fig. 6A);
  • Figs. 9A-9D are graphs illustrating the change in a third test subject's blood glucose level and the corresponding change in the amplitude of positive peak (parameter 1 of Fig. 6A);
  • Figs. 10A-10D are graphs illustrating the change in a fourth test subject's blood glucose level and the corresponding change in the amplitude of positive peak (parameter 1 of Fig. 6A);
  • Figs. 11A to 11F illustrate the experimental results for glucose concentration measurements (Figs. 11B to 11F) using a setup of Fig. 11A utilizing a magnet;
  • Figs. 12A-12B are graphs illustrating different functions indicative of a change in the speckle pattern over time generated by the system of the present invention, based on measurements before and after alcohol consumption;
  • Fig. 13 is a graph illustrating the pulse size (width) of the function indicative of skin vibration
  • Figs. 14A-14B are graphs illustrating the change of test subjects' pulse sizes over time, as a consequence of alcohol consumption
  • Fig. 15 is a graph illustrating the positive pulse size of the function indicative of skin vibration profile in the time domain
  • Figs. 16A-16B are graphs illustrating the change of test subjects' positive pulse sizes over time, as a consequence of alcohol consumption;
  • Fig. 17 is a graph illustrating the distance between peak polarities of the function indicative of skin vibration profile in the time domain;
  • Figs. 18A-18B are graphs illustrating the change of test subjects' distances between peak polarities over time, as a consequence of alcohol consumption;
  • Fig. 19 is a graph illustrating the main and secondary peak positions in the function indicative of skin vibration profile in the time domain
  • Figs. 20A-20B are graphs illustrating the change of test subjects' ratios between main and secondary peak positions, as a consequence of alcohol consumption;
  • Fig. 21 is a graph illustrating the main negative peak amplitude to the secondary positive peak amplitude in the function indicative of skin vibration profile in the time domain;
  • Figs. 22A-22B are graphs illustrating the change of test subjects' ratios between main and secondary peak positions, as a consequence of alcohol consumption;
  • Fig. 24 is a graph illustrating the change of test subjects' standard deviation in background noise, as a consequence of alcohol consumption
  • Figs. 25A and 25B present the results of one of the breathing experiments, and Fig. 25C shows a summary of the results of all 9 experiments, conducted by the inventors utilizing the system of the invention exemplified in Fig. IB;
  • Fig. 26 presents the results of the INR experiment conducted by the inventors utilizing the system of the invention exemplified in Fig. IB;
  • Figs. 27A to 27C present the experimental results for oxygen saturation measurements utilizing the system of the invention exemplified in Fig. IB, obtained for two saturation level experiments and compared with a reference measurement obtained using a convention pulse oxymeter;
  • Fig. 28 is a graph illustrating the oscillation amplitude of a function indicative of the eye's vibration as a function of intra-ocular pressure (IOP), where the function was generated via the system of Fig. IB using a lOmW laser;
  • IOP intra-ocular pressure
  • Fig. 29 is a graph illustrating a function indicative of the eye's vibration when
  • Fig. 30 is a graph illustrating amplitude of a function indicative of the eye's vibration as a function of intra-ocular pressure (IOP), where the function was generated via the system of Fig. IB using a 2mW laser;
  • Fig. 31 is a graph illustrating the oscillation amplitude a function indicative of the eye's vibration as a function of intra-ocular pressure (IOP), where the IOP was measured via a Goldmann tonometer; and
  • Fig. 32 is a graph illustrating the change of a test subject's pulse amplitude over time, as compared to the test subject's pulse blood pressure.
  • Fig. 1A is a block diagram of a system, generally designated 100, configured and operable according to the invention for use in monitoring one or more conditions of a subject's body.
  • the system 100 is configured as a computer system and includes an input port/utility 100A for receiving image data; a memory utility 100B for storing one or more predetermined models; a processor utility lOOC; and an output data utility 100D, for example associated with a display.
  • the system 100 is connectable (via wires or wireless signal transmission) to an imaging system or to a data storage utility, generally at 110, for receiving the input image data which is measured data in the form of a sequence of speckle patterns generated by a pixel detector array being indicative of an optical response of a portion of the subject's body to illumination by coherent light according to a certain sampling time pattern.
  • the imaging system 110 may be a motion measurement system configured generally similar to that of the above-indicated PCT Patent Publication WO2009/013738.
  • the memory utility 100B stores one or more predetermined models indicative of a relation between one or more measurable parameters and one or more conditions of the subject's body.
  • the processor utility lOOC is preprogrammed for processing the image data and utilizing one or more selected models to generate output data indicative of the one or more corresponding body conditions.
  • the processor utility analyzes the image data and determines a spatial correlation function between successive speckle patterns in the sequence, and a time varying spatial correlation function in the form of a time-varying function of at least one feature of the correlation function.
  • the time-varying spatial correlation function is indicative of a change of the speckle pattern over time.
  • at least one parameter of the time-varying spatial correlation function is selected, and one or more of the models is applied to this at least one parameter to determine one or more corresponding body conditions.
  • a system 200 for use in monitoring the subject's body condition(s), e.g. measuring at least one property of a 5 bodily fluid including a measurement unit 110 and a control unit configured as the above-described system 100.
  • the measurement unit 110 includes a source of coherent light 202 (e.g. laser source), an imaging unit having a pixel detector array (PDA) 111 and an imaging optics (e.g. single lens) 112.
  • the control unit 100 is connectable via wires or wireless signal transmission (e.g. RF, IR, acoustic) to the output of the PDA
  • control unit 10 111 may include an illumination controller for selecting appropriate wavelength(s) for illumination.
  • the source of coherent light 202 emits a light beam 104 to illuminate the object 102 during a certain time period (continuously or by multiple timely separated sessions).
  • the object constitutes a body region of a subject (e.g. individual) whose
  • movement is affected by a change in the body condition, typically a flow of a fluid of interest (i.e. a fluid having a property that is to be measured).
  • the object's diffusive surface responds to coherent illumination by a speckle pattern which propagates toward the imaging optics 112 and is captured by the PDA 111 during said certain time period, to generate output measured data.
  • the secondary speckle pattern is generated because of the diffusive surface of the object 102.
  • the speckle pattern propagates toward the in- focus plane 108, where it takes a form 106.
  • the speckle pattern propagates in a direction along the optical axis of the system, is collected by the imaging lens 112 and is collected by the PDA 111.
  • the detected speckle pattern changes phase. If the object 102 moves in the axial direction (toward and away from imaging lens 112), the detected speckle pattern changes scale. If the object 102 tilts (as shown in Fig. 2B), then the speckle pattern in the PDA plane shifts position. The scale and shape change as well as the position shift of the speckle pattern are detectable by the PDA, thereby allowing detection of the object's motion along the axial direction and tilting.
  • the speckle pattern is detected in the region A of the PDA 110, while in Fig. 2B following the tilt on the object's surface by an angle a, the speckle pattern illuminates and is detected by a region B of the PDA 111.
  • the relative shift of speckle pattern due to the displacement of the object's surface can be estimated as
  • ⁇ is proportional to the relative shift ⁇ of the speckle pattern (i.e. the distance between points A and B), a is the tilting angle of object's surface, and ⁇ is the optical wavelength. Assuming that the change in the angle is small enough, a linear proportion is obtained between the relative shift and the angle of tilting.
  • the object's movement causes changes in properties/profile (phase, magnification, position) of the speckle pattern detected by the PDA 110. Therefore, monitoring a change in the speckle pattern over time is associated with the movement of the object 102 and thus enables detection and characterization of the movement of the object 102.
  • the control unit 100 receives the measured data (or data indicative thereof and appropriately formatted) from the pixel(s) of the PDA 111 illuminated by the speckle pattern response of the object, and processes this measured data to form a spatial correlation function by determining correlation between successive images of the speckle pattern.
  • measured data is in the form of a sequence of speckle patterns generated by the object in response to coherent illumination according to a certain sampling time pattern - two such successively received speckle patterns being shown in Figs. 3A and 3B.
  • the control unit processes these speckle patterns and determines a correlation function between them, as exemplified in Fig. 3C being in the form of a correlation peak.
  • 3C represents the peak of the correlation function between the speckle patterns in Figs. 3A and 3B.
  • the control unit 100 is configured for extracting one or more features of the spatial correlation function (e.g. the shift in the correlation peak and/or the change of its value) and monitoring temporal changes of such extracted features, in order to construct data indicative of time variation in the correlation function.
  • the time variation in the correlation function is in turn indicative of variation of the speckle pattern, and therefore of motion in the illuminated body part, which causes such variation in the speckle pattern.
  • one or more parameters are extracted and used for determining one or more conditions of the body.
  • the optics 112 is slightly defocused with respect to the object's plane. This feature is important in order to convert the tilting movement of the object's surface into transversal movement of the speckles. This provides that the only varying property of the detected speckle pattern, returned from object that undergoes a tilting movement, is its position in the coordinate system of the PDA (i.e. pixel matrix) while other properties (phase and magnification) practically do not change during the tilting of the illuminated object.
  • a time function of the shift of such speckle pattern is tracked by the control unit which operates to apply a certain algorithm to the measured data for correlating the amplitude of the object's motion to the shift in the speckle pattern.
  • the speckle pattern shift along the PDA pixel matrix is indicative of the tilting movement of the object with respect to the optical axis
  • a change in the scaling (magnification) of the speckle pattern is indicative of the object's motion along the optical axis
  • a change in phase of the speckle pattern is indicative of the object's motion substantially perpendicular to the optical axis.
  • the amount of applied defocusing determines the amount of change in each one of the above mentioned properties.
  • one or more properties of a bodily fluid affect the motion of nearby body regions.
  • properties of flowing blood affect the motion of skin on a person's wrist.
  • the pressure of the aqueous humor i.e. the IOP
  • the intra cranial pressure affects the motion of the surface of the eardrum. Therefore, the temporal change in the correlation function (as indicated, for example by temporal change of the position and/or value of the obtained correlation function's peak) is indicative of properties (conditions) of the fluid of interest.
  • control unit 100 is configured to perform an analysis of the temporal variations of one or more features of the correlation function (such as the position and/or the value of the correlation peak), caused by time changes of the speckle pattern detected from the object during measurements. From the temporal change in the correlation function analysis, one or more parameters are extracted, these parameters being related to one or more properties of the fluid. The parameters are thus used to determine one or more properties of the fluid.
  • the correlation function such as the position and/or the value of the correlation peak
  • control unit 100 includes an input port 100A connected to the output of the PDA 111 and configured for receiving measured data indicative of the detected speckle pattern from the PDA's illuminated pixel(s), a processing utility lOOC (software/hardware utility), a memory utility 100B, and an output port 100D associated with a data presentation utility or an external storage device, as the case may be.
  • the control unit's processing utility lOOC is configured to construct the speckle pattern's spatial correlation function according to the data received from the PDA; the spatial correlation function data may be stored in the memory utility.
  • the processing utility lOOC includes appropriate functional modules for determining a spatial correlation function, analyzing the spatial correlation function and extracting one or more features thereof and tracking their variation over time, and constructing data related to the temporal change in the spatial correlation function. Subsequently, the processing utility lOOC utilizes a predetermined model (stored in the memory utility) selected for one or more body conditions to be monitored, and analyzes the temporal changes in the object's spatial correlation function according to the selected model. Generally, the model defines one or more sets of parameters (variables) of the temporal changes in the spatial correlation function, the parameters being associated with properties of a certain bodily fluid (e.g., via algorithm or look-up table).
  • the processor utility lOOC analyzes the spatial correlation function and identifies therein the values of one or more of the parameters. Once the parameters are extracted from temporal variations in the spatial correlation function, the processing utility lOOC operates for calculating one or more properties of the fluid, according to the selected model.
  • the second set parameters relating to the temporal change in the spatial correlation function may include an average amplitude of a sinusoidal vibration of the temporal change in the correlation function, and/or parameters describing peaks in the temporal change in the correlation function, e.g. the width of the first positive peak.
  • the output port 100D is configured for transmitting output data from the control unit to one or more output devices (e.g. display, printer, speaker), or to the monitor of 5 the control unit, in order to present data to a user.
  • the output data may include a graph of the temporal changes in the spatial correlation function and/or values of one or more of the extracted parameters, and/or values of one or more properties of the fluid.
  • the system 100 may be configured, inter alia, to determine blood-related parameters, such as concentration of substance in 10 blood (e.g. glucose concentration, blood alcohol concentration) and/or oxygen saturation, and/or blood flow volume (relative), blood pulse wave velocity, as well other bodily fluid related parameters such as intra-ocular pressure and/or intra-cranial pressure.
  • blood-related parameters such as concentration of substance in 10 blood (e.g. glucose concentration, blood alcohol concentration) and/or oxygen saturation, and/or blood flow volume (relative), blood pulse wave velocity, as well other bodily fluid related parameters such as intra-ocular pressure and/or intra-cranial pressure.
  • the measurement unit 110 may be configured as an endoscope for inspecting 15 internal organs.
  • the endoscope may be of any known suitable configuration, in which, for the purposes of the present invention, an optical assembly is configured for setting a predetermined defocus between the surface of the internal organ and the detector array.
  • Fig. 4 shows specific but not limiting example a system of the present invention 20 300 formed by the above-described control unit 100 and a measurement unit 110 including an endoscope-based imaging system configured for providing measured data in the form of a sequence of speckle response to coherent de -focused illumination.
  • the system 300 is adapted for monitoring biomedical parameter of an internal organ (object) 102.
  • the measurement unit 110 includes a source of coherent light 202, a detector array 25 111 (e.g. including a CCD), an optical assembly 112, and a light guiding unit 20.
  • the light guiding unit 20 is configured as a micro probe that transfers light arriving from the internal organ 2 to an input edge (distal tip) 21 of the micro probe 20 toward an output edge 22 (proximal tip) of the micro probe 20.
  • the optical assembly 112 may be configured to collect light at the output edge 22 of the micro probe 20 and 30 to form a defocused image of a surface of the internal organ 102 on the pixel detector array 111.
  • the optical assembly may comprise one or more lenses, as well as may be displaceable along an optical axis ⁇ so as to be capable of performing defocused imaging of an object at variable distance of the input edge 21 of the micro probe 20.
  • the micro probe 20 may actually be regarded as if the input and output edges 21, 22 of the micro probe 20 act similarly to principle planes of a lens, the position of the optical assembly 30 in order to obtain focused imaging may be determined according to the following relation:
  • Ui is the distance between the internal organ 102 and the input edge 21 of the micro probe 20
  • L is the distance between the output edge 22 of the micro probe 20
  • V is the distance between an optical center of the optical assembly 112 and the detection array 10
  • F is the focal length of the optical assembly 112.
  • the above position of the optical assembly 112 obtained using the abovementioned relation is not respected so that a slight defocusing exists.
  • the distance between the optical assembly 112 and the detector array 111 is different than the distance V obtained using the relation abovementioned.
  • the micro probe 20 may be a multicore fiber.
  • the diameter of a core and the diameter of the multicore fiber 20 may be respectively referred to as d and D.
  • the values of d and D are defined by fabrication and application related limitations. For example, D may be smaller than 300 ⁇ in order to remain non invasive in certain medical applications.
  • the value of d may be determined according to a desired spatial resolution. If D is equal to 300 ⁇ and one wishes to have 100x100 pixels resolution it means that d may be about 3 ⁇ .
  • d may be larger than an optical wavelength of the light collected in order to allow coupling of light to the fiber with sufficient energetic efficiency.
  • the illumination source 202 is a source of coherent light and is configured to inject an illumination beam into the input edge 21 of the micro probe 20 so that a speckle pattern can be generated at a surface of the internal organ 102.
  • the speckle pattern generated may propagate back toward the input edge 21 of the micro probe 20 to the output edge 22 of the micro probe 20.
  • the optical assembly 112 may perform defocused imaging of the speckle pattern on the detector array 111.
  • control unit 100 may be connected to an output of the detector array 111 via wires or wireless signal transmission (e.g. RF, IR, acoustic, etc.) and in some embodiments, the processing unit may be associated with the light source for selecting one or more appropriate wavelengths for illumination.
  • the processing unit lOOC may receive image data from the pixels of the pixel detector array 111 illuminated by the speckle pattern, and process the image data to calculate a correlation function between successive images of the speckle pattern. Two such successively received speckle patterns are exemplified in Figs. 3A and 3B described above, and the correlation function between them is exemplified in Fig. 3C being in the form of a correlation peak.
  • control unit 100 is configured to apply component analysis in order to characterize and separate between the temporal characteristics of the correlation peak for reflections related to different values of the inspected biomedical parameters.
  • infected tissues have different temporal variations profile of speckle pattern correlation peak with respect to non-infected tissue. Basically each one of them may have its own correlation peak "signature".
  • signature refers for instance to the shape, amplitude value and/or the ratio between positive and negative pulse width and etc.
  • the severity level of the disease will act and affect differently the speckle pattern which in turn may have different type of signature.
  • the definition of the disease severity can be evaluated or defined for instance by a "lookup table".
  • the system may further include an ultrasound device configured to excite the inspected organ.
  • the multicore fiber may be a fiber bundle or a photonic crystal, and may have a polygonal or substantially circular cross section defining two opposite substantially parallel facets.
  • the optical assembly 112 is slightly defocused with respect to the organ surface plane and to the detector array plane. This feature enables to convert the tilting movement of the organ's surface into transversal movement of the speckles. This provides that the only varying property of the detected speckle pattern, returned from the organ that undergoes a tilting movement, is its position in the coordinate system of the PDA (i.e. pixel matrix) while other properties (phase and magnification) practically do not change during the tilting of the illuminated organ. A time function of the shift of such speckle pattern is tracked by the control unit which operates to apply a certain algorithm to the measured data for correlating the amplitude of the organ's motion to the shift in the speckle pattern.
  • the control unit which operates to apply a certain algorithm to the measured data for correlating the amplitude of the organ's motion to the shift in the speckle pattern.
  • the speckle pattern shift along the PDA pixel matrix is indicative of the tilting movement of the object with respect to the optical axis, while a change in the scaling (magnification) of the speckle pattern is indicative of the object's motion along the optical axis.
  • the amount of applied defocusing determines the amount of change in each one of the above mentioned properties.
  • one or more properties of a fluid in an organ affect the motion of the organ.
  • properties of flowing blood affect the motion of the heart. Therefore, the temporal change in the correlation function (as indicated, for example by temporal change of the position and/or value of the obtained correlation function's peak) is indicative of properties (conditions) of the fluid of interest. Therefore, analysis of the temporal variations of one or more features of the correlation function (such as the position and/or the value of the correlation peak), caused by time changes of the speckle pattern detected from the organ during measurements, enables to extract one or more attributes related to one or more properties of the fluid. The attributes are thus used to determine one or more properties of the fluid.
  • the output data generated by the control unit 100 of the invention may include a graph of the temporal changes in the spatial correlation function and/or values of one or more of the extracted parameters, and/or values of one or more properties of the fluid.
  • the system of the invention may be configured, inter alia, to monitor local blood-related parameters of an internal organ, such as internal blood pressure of a blood vessel, concentration of substance in blood (e.g. glucose concentration, hemoglobin concentration) and/or oxygen saturation, and/or blood flow volume (relative), blood pulse wave velocity, temperature.
  • concentration of substance in blood e.g. glucose concentration, hemoglobin concentration
  • oxygen saturation e.g., glucose concentration, hemoglobin concentration
  • blood flow volume e.g., blood pulse wave velocity
  • the system may also be configured for other medical application as reminded in the general description section.
  • a flowchart 400 exemplifies a method of the present invention for measuring a property of a fluid.
  • a function indicative of the speckle pattern profile over time is provided and analyzed, in order to extract one or more parameters relating to the temporal shape of the spatial correlation function (as described, for example, by the temporal change in the position of spatial correlation function's peak or the temporal change in the value of this peak), in accordance to the body condition(s) to be monitored.
  • the extracted parameter(s) is (are) used to determine one or more properties of the bodily fluid according to a predetermined model, and to generate output data indicative of the property of the bodily fluid.
  • the temporal change in the correlation function may be provided off-line from another processor or storage device, or as exemplified in the figure, may be provided in an on-line mode by processing and analyzing measured data (speckle patterns) from an optical measurement device at 306, 308 and 310.
  • the region of interest is illuminated by coherent light over a certain time period.
  • a speckle pattern response to the coherent light is detected, and images of the speckle pattern are recorded over time. Consequently, at 310, the images of the speckle pattern are analyzed to determine one or more characteristics (e.g., position and/or shape) of the speckle pattern. Change in the one or more speckle pattern characteristics is determined between subsequent images, to construct a spatial correlation function of the speckle pattern over the measurement time.
  • One or more features of the spatial correlation function (e.g. a position of the correlation function's peak and/or a value of the correlation function's peak) are extracted and monitored over time, in order to construct data indicative of the temporal change of the spatial correlation function.
  • the so-estimated temporal change in the correlation function can then be analyzed in step 302.
  • the inventors have conducted various experiments demonstrating the capability of the technique of the present invention for monitoring various subject's parameters/conditions, including for example glucose concentration in blood stream, breathing, coagulation, oximerty, as well as blood alcohol concentration, measurement of intra-ocular pressure, dehydration, monitoring of cattle, temperature, flow velocity and volume.
  • the system of the invention can monitor several vital biomedical parameters simultaneously, and also can be realized in a very simple and cost efficient manner involving simple camera and a laser source.
  • the technique is based on the tracking of temporal changes of reflected secondary speckle produced in a region of interest in the subject when being illuminated by a laser beam. A temporal change in the vibration profile of the region of interest generated due to fluid (e.g. blood) pulsation is analyzed for estimating the desired parameter (e.g. glucose concentration).
  • Speckle or speckle pattern may be produced in spatially coherent light due to self interference within the laser beam, while the temporal trajectories of the speckle patterns that are captured by the camera are proportional to the temporal signals that are to be extracted (a vibration profile).
  • a self-interference pattern is constructed on the CCD plane of the observing camera.
  • a temporal change in the pattern is related to a relative spatial shift between two adjacent frames taken by the camera.
  • the following section refers to test conducted by the inventors on human subjects, in order to determine a relationship between blood glucose concentration and parameters of the time varying function indicative of the time changes of the speckle pattern caused by vibration of skin on the subjects' wrists (i.e. the temporal change in the spatial correlation function).
  • C v (t) is the venous glucose concentration at time t
  • F is the blood flow (represents the amount of blood, usually in litters per minute)
  • q 0 corresponds to a glucose pulse and represents the amount of glucose (in mg) in the blood (in Kg) per heart beat
  • ⁇ is the fraction of the glucose pulse that is extracted from the blood system and is metabolized (therefore it will never be recovered at the outlet of the vein)
  • h(t) is the reversible fates of glucose in the organ that causes a delay and a distortion in the appearance of glucose pulse in the vein.
  • a vibration profile of a blood vessel is a unique one. It is characterized by many individual parameters, such as vessel elasticity, human fat layer, blood viscosity etc. Therefore any change of one of these parameters affects a change of this vibration profile. Changes in glucose level in blood affect the viscosity of blood, while a change in viscosity of blood affects the friction between the blood and the vessel walls, while a change in the friction in turn affects the motion profile. Thus, a change of friction due to a change in glucose concentration in the arteries and veins causes a change of the vibration profile of the vessel.
  • the inventors In order to determine glucose concentration from the analysis of the vibration profile of skin on a human wrist, the inventors have analyzed the temporal changes in a spatial correlation function corresponding to the time variations of the speckle pattern in the successive images, by observing quantitative parameters of the temporal changes in a spatial correlation function before and after glucose intake.
  • the temporal changes in the spatial correlation function were in the form of the temporal variations of the spatial correlation function's peak and/or in the temporal variations of the value of the peak of the spatial correlation function.
  • Such parameters were compared to the actual glucose level in the blood that is obtained via a reference measurement with conventional techniques.
  • An experimental system was constructed similar to the above-described system of Fig. IB, and used to illuminate a wrist of a subject being fixed by gypsum to allow more accurate measurement.
  • the source of coherent light was a green laser (having wavelength of 532nm).
  • the laser output power was about lOmW.
  • An imaging optics of the camera was slightly defocused.
  • the focal length of the optics that was used in the experiments was 50mm and the distance from the laser to the subject's hand was about 50cm.
  • the camera captured images of the secondary speckle pattern from the wrist of the subject at rate of 350 frames per second (fps).
  • a detected system output with high signal to noise ratio illustrates temporal change in the spatial correlation function indicative of the vibration profile of skin in a human wrist obtained in this experiment.
  • the graph of Fig. 6A includes only several pulses, while in the experiment six pulses were taken into consideration and averaged. It can be seen that every pulse is shaped similarly to electrocardiogram (ECG) PQRST-type pulse. It contains a P pulse, QRS complex, and a T pulse. However, this is a function indicative of a mechanical vibration profile, rather than an electrical signal (as ECG), and therefore it corresponds to temporal information about vibration of blood vessels (proximal to the illuminated skin) due to blood flux pulsation.
  • ECG electrocardiogram
  • the following parameters of the temporal change in the position of the peak of the spatial correlation function have been monitored: the main temporal peak amplitude (positive and negative) during one heart beat, temporal pulse width (positive and negative), temporal pulse profile energy (positive and negative separately), mean temporal distance between temporal peaks (gap or pulse rate), positive to negative temporal pulse peak ratio, temporal distance from positive to negative temporal peak, secondary temporal peak amplitude and main to secondary temporal peak amplitude ratio.
  • the main temporal peak amplitude positive and negative
  • temporal pulse width positive and negative
  • temporal pulse profile energy positive and negative separately
  • mean temporal distance between temporal peaks gap or pulse rate
  • positive to negative temporal pulse peak ratio temporal distance from positive to negative temporal peak
  • secondary temporal peak amplitude and main to secondary temporal peak amplitude ratio are listed in Table 1 below, and the reference numerals in Table 1 refer to the numerals present in Fig. 6A.
  • Table 1 Parameters of the temporal change in the location of the peak of the spatial correlation function
  • a second check test was aimed to check the stability of the gypsum fixation over time. Each subject inserted his/her hand into the fixation device and stayed fixed for approximately 30 minutes, while he/she was monitored by the system. The result of the second test is illustrated in Fig. 6B where the stability of the system can be clearly seen, since the measured values' results do not vary more than 15%.
  • Substantially constant glucose concentration corresponded to substantially constant negative pulse width (parameter 6 of Fig. 6A) of the time variations in the position of the spatial correlation's function peak.
  • Glucose concentration is shown by line Li in units of [ml/dl] divided by 10 (representing a constant level of 100 [ml/dl]), while the parameter 6 is shown by line Li.
  • the units of parameter 6 are counted in time samples (each sample is 1/rate in time units).
  • the actual measurement was performed to relate parameters of the temporal changes in the position of the peak of the spatial correlation function to be indicative of the wrist's temporal pulse profile to glucose concentration in blood.
  • each examined subject preserved a fast for about 12 hours before the measurement took place.
  • the expected values of blood glucose level for non-diabetic person after fasting falls to values range between 90 to 110 [mg/dl].
  • the subject's blood glucose level was at this range, while later the subject received a sweetened drink and the level was changed.
  • the rate at which the concentration of glucose increases is different for each individual and depends on many personal parameters, such as body weight, metabolic rate, level of insulin in blood etc.
  • the blood glucose level reached by the test subjects after drinking of about 400ml of sweetened beverage (40K Cal) was in the range between 150 and 190 [mg/dL].
  • Each experiment lasted for 50-80 minutes, during it the measurements were carried out repeatedly every 5 minutes.
  • Each 5 minutes sampling included capturing six subsequent video files of the illuminated spot and taking an accurate blood sample with a glucometer ("Accu-check") and manual blood pressure measurement using standard sphygmomanometer. All experiments showed that blood pressure did not change over the time of the experiment. It was important to check that blood pressure remained unchanged, in order to ensure that the expected change in the temporal pulse profile of the position of the speckle pattern's spatial correlation function's peak was indeed caused by glucose intake, rather than by blood pressure change.
  • a MATLAB program analyzed the videos and extracted the observed parameters from the files.
  • Each file contained about 5 seconds of video samples at rate of 350 fps (frames per second), enabling the construction of data indicative of the temporal variation in position of the speckle pattern's spatial correlation function's peak, usually containing 6 temporal pulse peaks.
  • Each peak was processed separately and the chosen parameters were extracted and averaged, therefore representing the average of approximately 30 peaks of pulse profile per each 5 minutes.
  • the final graph of the estimated glucose level was produced. Joint graphs of the estimated and the reference glucose level for each one of the parameters and for each one of the subjects were created.
  • the calculation include estimation of a correlation coefficient C fg (which is also called the value of the correlation peak) between optically extracted parameter of the and true glucose concentration obtained via the reference measurement. It is important to mention that this correlation coefficient is not related to correlation function between speckle patterns. Rather, this correlation coefficient is an estimate of the level of correlation between the optically extracted parameter (i.e. the parameter of the temporal change of the spatial correlation function) and the glucose concentration obtained via the reference measurement. A correlation coefficient approaching 1 or -1 is indicative of good correlation between the optically extracted parameter and the glucose concentration. If the correlation coefficient near 0, little or no correlation exists between the optically extracted parameter and the glucose concentration.
  • the correlation coefficient or the value of the correlation peak equals to:
  • RMSE root mean square error
  • Xj is an i-th sample of the parameter values
  • i3 ⁇ 4 is an i-th sample of the reference glucose measurements
  • N is the number of samples.
  • the calculated samples were normalized to have energy of 1, before applying the RMSE estimator in order to obtain the common estimation scale for all parameters.
  • Glucose concentration in blood is denoted by the lines with triangles and the optically measured parameters from the pulse profile are denoted by the lines with squares.
  • the graph of the reference (glucose level) was obtained by using a conventional glucose meter device ("Acuu-check"). Error bars refer to standard deviation of positive and negative deviations separately, calculated over each 30 peak samples (per each point on the graph).
  • Four different graphs on each figure refer to four different experiments taken with relevant subject on different days, during the morning hours while each subject preserved a fast of 12 hours. Values of the extracted parameters were linearly transformed to glucose level units according to the calibration done per each subject at the first measurement (time 0). Correlation and RMSE coefficients are shown below each graph.
  • the inventors have thus demonstrated that a strong correlation coefficient exists between the glucose blood concentration in the internal organ and attribute 1. Therefore, it is possible to establish a linear dependency between the amplitude of positive peak amplitude in the variation of the position of the correlation peak and the glucose blood concentration.
  • Figs. 6C-6F are graphs illustrating the change in a test subject's blood glucose level and the corresponding change in the amplitude of positive peak (parameter/attribute 1 of Fig. 6A).
  • Figs. 7A-7D are graphs illustrating the change in a test subject's blood glucose level and the corresponding change in the ratio between positive and negative peak amplitudes (parameter 9 of Fig. 6A).
  • Figs. 8A-8D are graphs illustrating the change in a second test subject's blood glucose level and the corresponding change in the amplitude of positive peak (parameter 1 of Fig. 6A).
  • Figs. 6C-6F are graphs illustrating the change in a test subject's blood glucose level and the corresponding change in the amplitude of positive peak (parameter/attribute 1 of Fig. 6A).
  • Figs. 7A-7D are graphs illustrating the change in a test subject's blood glucose level and the corresponding change in the ratio between positive
  • FIGS. 9A-9D are graphs illustrating the change in a third test subject's blood glucose level and the corresponding change in the amplitude of positive peak (parameter 1 of Fig. 6A).
  • Figs. 10A-10D are graphs illustrating the change in a fourth test subject's blood glucose level and the corresponding change in the amplitude of positive peak (parameter 1 of Fig. 6A).
  • Figs. 6C-6F refer to subject 1.
  • the best correlative parameter for this subject was parameter 1.
  • Figs. 7A-7D show an exact inverse ratio between the reference glucose level and the value of parameter 9. Note that parameter 9 is actually a ratio between parameters 1 and 5. Some of the results showed very high correlation with the reference measurement for the full cycle of glucose changes in blood. In Fig. 7B it can be see that parameter 9 tracks the reference glucose level (in opposite direction).
  • the time profile of parameter 9 includes areas in which the slope is positive and areas in which the slope is negative, thereby presenting a full cycle of increase and decrease of glucose level in the blood. A correlation coefficient of -0.916 was obtained between the two curves.
  • RMSE estimator for this parameter was calculated between the inverse function of the normalized estimated parameter (one minus the normalized values) and the reference. RMSE estimator is equal to 0.17 in this case.
  • Figs. 8A-8D refer to subject 2. The best correlative parameter for this subject was found to be positive pulse amplitude (parameter 1).
  • Figs. 9A-9D refer to subject 3. The best correlative parameter for this subject was found to be parameter 1 as well.
  • Figs. 10A-10D refer to subject 4, with the best correlative parameter 1.
  • RMSE estimator coefficients from the graphs presented in Figs. 6C-6F, 7A-7D, 8A-8D, 9A-9D, 10A-10D.
  • the technique of the present invention has been shown to provide an optical remote configuration for the estimation of glucose concentration in blood.
  • the system of the present invention was tested with clinical trial group and the estimated results show a high correlation and low error comparing to reference measurement obtained by conventional invasive means.
  • the technique of the present invention it was demonstrated that at least one parameter extracted from data indicative of the temporal change of the spatial correlation function between speckle patterns obtained via measurements of speckle patterns generated from the wrist is proportional to the change of glucose concentration in blood.
  • the technique of the present invention provides a non-invasive manner of remote measurement of glucose concentration in blood, while it uses only a low power emitting laser and a camera.
  • Fig. 11A illustrates the experimental setup for glucose level measurements.
  • the experimental system is constructed generally similar to the above-described system of Fig. 1A, namely includes a measurement unit 110 (camera) and a control unit (computer) 100, and used to illuminate a wrist of a subject.
  • the measurement system is carried by bracelet-like holder 120 mountable on a patient's wrist.
  • a magnet 130 can be used, being placed between the patient's wrist and the measurement unit. This is in order to determine very small changes in the rotation produced by magneto-optic materials.
  • the glucose exhibits the Faraday effect which is generated due to the circular structure of the glucose molecule.
  • the magnet When a magnet is added to the setup (e.g., the bracelet-like design), the magnet generates magnetic field, and due to the Faraday effect there is a modification of the speckle pattern due to the existence of the glucose molecules. As other materials do not exhibit the Faraday effect, the change in the speckle pattern caused only due to the concentration of the glucose can be allocated. This yields much higher accuracy in the estimation of the glucose concentration.
  • the source of coherent light is a green laser (having wavelength of 532nm).
  • the laser output power is about lOmW.
  • An imaging optics of the camera is slightly defocused.
  • the focal length of the optics that is used in the experiments is 50mm and the distance from the laser to the subject's wrist is about 50cm.
  • the camera captured images of the secondary speckle pattern from the wrist of the subject at rate of 350 frames per second (fps). After extracting the speckle pattern in each frame, correlation was performed and the change in the 2-D position of the peak versus time was obtained. Every pulse is shaped similarly to ECG PQRST, in the experiment the average of five pulses was taken into account.
  • the inventors used MATLAB software product modified to a new factor which is the Faraday effect and its influence on the speckle field, to analyze the videos obtained from the camera and extract the observed parameters from the files.
  • the algorithm analyzes the difference between two subsequent frames in means of lateral shift of speckle pattern using a correlation technique, therefore per one frame one value of the shift profile is produced. Once the vibration profile is obtained the pulsation shift peak is considered. In some cases the temporal change of the pulsation profile is analyzed.
  • Each file contained about 5 seconds of video samples at rate of 545 fps (frames per second), usually containing 8 pulse peaks. Each peak is processed separately and the chosen parameters are extracted and averaged, therefore representing the average of approximately 30 peaks of pulse profile per each 5 minutes.
  • the main measured parameter was the maximum pulse amplitude that refers to highest amplitude during one heart beat.
  • Fig. 11B shows one of the ECG measurements obtained by the bracelet-like setup with magnet shown in Fig. 6C, this graph is used us to monitor the glucose concentration and the dehydration level.
  • a MATLAB software program was used that analyzed the videos obtained from the camera and extract the observed parameters from the files. Each file contained about 5 seconds of video samples at rate of 545 fps (frames per second), usually containing 8 pulse peaks. Each peak is processed separately and the chosen parameters are extracted and averaged, therefore representing the average of approximately 30 peaks of pulse profile per each 5 minutes.
  • the main measured parameter was the maximum pulse amplitude that refers to highest amplitude during one heart beat.
  • each examined subject preserved an overnight fast for about 12 hours before the measurement took place.
  • the expected values of blood glucose level for non-diabetic person after fasting falls to values range between 90 to 110 [mg/dl].
  • the rate at which the concentration of glucose increases is different for each individual and depends on many personal parameters, like body weight, metabolic rate, level of insulin in blood, etc.
  • the blood glucose level obtained after drinking of 500ml of sweetened beverage (195 Cal) by the subjects was from 130 tol60 [mg/dL].
  • Each experiment lasted for 50-80 minutes, during it the measurements were carried out repeatedly every 5 minutes.
  • Each 5 minutes sampling included capturing four subsequent video files of the illuminated spot and taking an accurate blood sample with a glucometer ("Accu-check”) and manual blood pressure measurement using standard sphygmomanometer. All experiments showed that blood pressure have not been changed over the time of the experiment, which is important to check this point in order to ensure that the expected change in the pulse profile is indeed caused by glucose intake, rather than by blood pressure change.
  • Figs. 11C-11F show glucose level in blood and the maximum amplitude peak
  • Glucose level is denoted by curve Pi (red) and the optically measured parameter is denoted by curve P2 (blue).
  • the graph of the reference (glucose level) was obtained by using a conventional glucose meter device ("Acuu-check"). Four different graphs refer to four different experiments taken on different days, during the morning hours while
  • each subject preserved a fast of 12 hours.
  • Estimated values were linearly transformed to glucose level units according to the calibration done per each subject at the first measurement (time 0).
  • the standard deviation was measured between the optical measure of the invention to the reference. As shown, there is a tracking of the glucose level by the optically measured parameter, the optical measurement tracks up and falls
  • the following section refers to tests conducted by the inventors on human subjects, in order to determine a relationship between blood alcohol concentration and 20 one or more parameters of the temporal changes in a feature (e.g. the correlation peak and/or its value) of the speckle pattern's spatial correlation function in the time domain.
  • a feature e.g. the correlation peak and/or its value
  • the tests were conducted with an experimental system generally similar to that of Fig. Undesigned as the above described bracelet- like setup.
  • the experimental system included only a green laser to illuminate the inspected object (to generate the 25 secondary reflected speckle) and a defocused camera connected to a computer (control unit) that observes the secondary speckle pattern reflected from the wrist of the subject.
  • the distance from the laser to the subject's wrist was about 10cm.
  • the sampling rate of the camera was 405 FPS (frame per second).
  • the coherent light emitter was a green CW (continuous wave) laser at a wavelength of 30 532nm at an approximate power of lOOmW.
  • the laser beam incidence angle was chosen to be 75 degrees relative to the subject's wrist.
  • the samples taken during the tests were in the form of an AVI file (video file) that shows the speckles pattern through time.
  • AVI file video file
  • the inventors located the position of the 2-D speckles pattern at each frame.
  • the Matlab program first removed background static noise by comparing the adjacent frames, then analyzed the shift in the speckles between adjacent frames to create data indicative of the skin (and therefore vascular) movement.
  • a spatial correlation function between speckle patterns in adjacent frames was determined. Then, the X and Y coordinates of the position of the spatial correlation function's peak were plotted for each frame, and the shift of such peak between adjacent frames was determined, to create a time- varying function indicative of the temporal change of the spatial correlation function, and of the skin (and therefore vascular) movement.
  • the plots were analyzed and several parameters were extracted from the time-varying function.
  • the parameters of the time-varying function included the main peak amplitude, distance between two nearby peaks, ratio between main and secondary peaks amplitude, etc. A total of 19 different parameters were extracted. Every AVI file provided six different temporal pulses and also the average values of the parameters of the six pulses. All this data was plotted as an excel output data table. Each time, five samples of each test were taken and averaged.
  • each of the subjects was seated in front of the experimental system, while his wrist was illuminated by the laser beam.
  • the arm of each test subject was tied and fixed to the system, in order to ensure that the subject's pulse would not be affected by any other external variables (such as involuntary movement) and thereby to increase of the accuracy of the measurements.
  • Figs. 12A-12B there are shown different time-varying functions indicative of time changes in the position of the speckle pattern (due to a motion of skin on a human wrist) as generated by the system of the present invention, based on measurements before alcohol consumption (Fig. 12A) and after alcohol consumption (Fig. 12B).
  • Figs. 14A-14B are graphs illustrating the change of test subjects' pulse sizes over time, as a consequence of alcohol consumption.
  • the pulse size is the width of the main pulse at the level at which the shift's amplitude is zero. The units of this parameter are milliseconds.
  • the pulse size is the amount of time that the outer layers of the blood vessels are subjected to the largest shift.
  • Table 6 summarizes values the of pulse size before drinking alcohol and after significant time (25 min & 35 min).
  • Table 7 summarizes the values of the pulse size in the long duration test, where measurements were taken before drinking alcohol and every 15 min thereafter (for 75 min).
  • Figs. 16A-16B are graphs illustrating the change of test subjects' positive pulse sizes over time, as a consequence of alcohol consumption.
  • the positive pulse size is the width of the positive pulse (relative to the main peak) at the level at which the shift's amplitude is zero.
  • the units of this parameter are milliseconds.
  • Table 8 summarizes values the of positive pulse size before drinking alcohol and after significant time (25 min & 35 min).
  • Table 9 summarizes the values of the pulse size in the long duration test, where measurements were taken before drinking alcohol and every 15 min thereafter (for 75 min).
  • Figs. 18A-18B are graphs illustrating the change of test subjects' distances between peak polarities over time, as a consequence of alcohol consumption.
  • peak polarities also referred to as “peakdis”
  • This parameter is measured in milliseconds.
  • Table 10 summarizes values of the distance between peak polarities before drinking alcohol and after significant time (25 min & 35 min).
  • Table 11 summarizes the values of the distance between peak polarities in the long duration test, where measurements were taken before drinking alcohol and every 15 min thereafter (for 75 min).
  • FIGs. 20A-20B are graphs illustrating the change of test subjects' ratios between main and secondary peak positions, as a consequence of alcohol consumption. The ratio between the main and the secondary peak position is without units.
  • Table 12 summarizes values of ratios between main and secondary peak positions before drinking alcohol and after significant time (25 min & 35 min).
  • Table 13 summarizes the values of ratios between main and secondary peak positions in the long duration test, where measurements were taken before drinking alcohol and every 15 min thereafter (for 75 min). The data of tables 12 and 13 is shown graphically in Figs. 19A and 19B, respectively.
  • Figs. 22A-22B are graphs illustrating the change of test subjects' ratios between main and secondary peak amplitudes, as a consequence of alcohol consumption.
  • Table 14 summarizes values of ratios between main and secondary peak amplitudes before drinking alcohol and after significant time (25 min & 35 min).
  • Table 15 summarizes the values of ratios between main and secondary peak amplitudes in the long duration test, where measurements were taken before drinking alcohol and every 15 min thereafter (for 75 min). The data of tables 14 and 15 is shown graphically in Figs. 22A and 22B, respectively.
  • Fig. 24 is a graph illustrating the change of test subjects' standard deviation of background noise, as a consequence of alcohol consumption.
  • the present invention can be also used for measuring alcohol level in the blood.
  • the advantage provided by the technique of the present invention lies in the fact that the present technique enables real-time and non invasive estimation of alcohol in the bloodstream. This is in contrast with the known breath analysis technique, which is less reliable since it measures low concentrations of alcohol in breath.
  • the inventors have also conducted experiments for measuring breathing, blood coagulation and oxymetry using the technique of the present invention.
  • the experimental setup used in these experiments was generally similar to the system of Fig. IB, and in some cases a beam expander was also used.
  • the system includes a laser, fast digital camera with its imaging lens and a computer to process the sensed images. All experiments were done twice by using two laser systems for comparison purposes. The first is a visible laser (Nd:YAG laser with wavelength of 532nm) and the second is a non-visible IR (Infra-Red) laser at wavelength of 1550nm. The two systems produced similar results.
  • a visible laser Nd:YAG laser with wavelength of 532nm
  • a non-visible IR (Infra-Red) laser at wavelength of 1550nm.
  • the two systems produced similar results.
  • a digital PixelLink model number A741 camera was used for the system using a visible laser. The camera captures images of the secondary speckle patterns being reflected from the chest of the subject at rate of about 2200 frames per second (fps).
  • the focal length of the optics used in the experiments was 150 mm for the 532nm laser system and 600 mm for the IR system.
  • the distance from the laser to the subject's chest was about 40m.
  • the laser output power was about 50m W.
  • a beam expander x3 was used.
  • an IR laser at 1550nm was used for eye safety reasons and the model of the camera was changed to EHD-IK112.
  • the sampling rate of the camera depended on the specific experiment and varied from 20 fps up to about 2000 fps. In all cases the experiments were performed on healthy female swine models - domestic mixed breed of large white and landrace pigs having weight of around 50 kg. These animals are similar in blood circulation, heart, skin and digestive systems to humans. Ten experiments were performed for a different swine in each experiment. The swine were anesthetized and put under artificial respiration.
  • Pulse and breathing rates were measured on a time scale but the results of all the other parameters are extracted from the value of the amplitude of the movement. Therefore, the invention provides for monitoring simultaneously both the pulse and breathing rate and one or more additional parameters. Since each of the parameters has special characteristics (amplitude value and shape) and since the invention provides for tracing nanometric movements, it is possible to measure multiple parameters simultaneously.
  • a calibration process is generally needed to perform remote biomedical estimation.
  • the calibration is basically finding the translation factor that may translate the optical measurement done in pixels to the absolute value of the specific biomedical parameter. This is indeed done by equating the readings from the surgery room equipment to the optical readout. Indeed the calibration may depend on the location from which the measurement is done. However, the inventors have found that the measurements are very repeatable. The inventors conducted experiments while placing the measurement system on a tracker so the system is able to measure the relevant biomedical parameters on a moving subject and each time the measurement were extracted from the same location.
  • Breathing is the process of supplying oxygen to the body and removing carbon dioxide from it, while its rate is the number of breaths taken per minute. The normal rate for adults is 12-20 breaths per minute.
  • the measurement was done by processing reflections from the swine's chest.
  • the measurements involved correlation of the time varied speckle patterns and plotting the amplitude of the relative shift of the correlation peak versus time.
  • the reference measurement was done with a respirator, while the number of breaths per minute was controlled and changed in each measurement (within the range of 13-20 breaths per minute).
  • the data analysis algorithms allow to isolate the heart rate as well as the other parameters and to filter out the breathing movements from the results.
  • the results presented below are the heart beats and they are not affected by the breathing.
  • the filtering was done by inspecting the spectrum domain, identifying the breathing frequency and then removing it from the temporal signal. In the breathing experiment, measurement were performed with and without the respirator and it was shown that there is no significant difference in measuring breathing when the subject breaths freely.
  • FIGs. 25A and 25B present the results of one of the breathing experiments (experiment no. 1) and a summary of the results of all 9 experiments are presented in Fig. 25C.
  • the experiment has demonstrated almost perfect correlation (99.7%) between the optical device and the reference measurement (respirator).
  • the breathing experiment is summarized in Table 17. Table 17:
  • TNR Coagulation of blood
  • the technique of the present invention can also be used to determine a coagulation condition of blood.
  • Coagulation is the process in which the blood forms clots after an injury in order to stop the bleeding and heal the injury.
  • the process involves two components - platelets and proteins which are known as clotting factors.
  • the platelets form around the injury site and at the same time proteins in the blood plasma respond to form fibrin and strengthen the platelet plug.
  • Disorders of coagulation occur when there is a deficiency or abnormality in one of the clotting factors or platelets. There can be either increased tendency for excessive clotting (thrombosis) or an increased risk of bleeding (hemorrhage). Blood coagulation disorders can be either inherited or a result of another disease or a side effect of medications.
  • PT test Prothrombin Time
  • INR International Normalized Ratio
  • ISI International Sensitivity Index
  • the ISI value indicates how a particular batch of tissue factor compares to an international reference tissue factor.
  • the ISI is usually between 1.0 and 2.0.
  • INR The normal INR value is close to 1 and is higher for patients who take anticoagulant medication and need to be monitored regularly (usually between 2 to 3). INR can be monitored either by a blood test or by portable monitoring device which requires a drop of blood sampled from the fingertip and inserted into the device.
  • the reference measurement for coagulation used in the experiments conducted by the inventors was done with the automatic INR measurement using CoaguCheck XP device.
  • the swine got two shots of Herafin, while each 5 min the INR level was monitored.
  • a pulse profile was distinguished out of the time evolution of the vibrations of the body due to blood vascular activity.
  • the experimental procedure was similar to the previous ones. The results were analyzed from the heart rate peaks and it's amplitude's shape and value. More specifically, a system similar to that of Fig. IB was used to illuminate a portion of the skin. Variations in the speckle pattern were detected and processed as described above to determine a correlation function and a time variation of a feature (e.g., peak position and/or peak size) of the correlation function. Indeed, since a change in coagulation directly affects the viscosity of the blood, a change in coagulation strongly affects the mechanical movement of the surface of the skin that may be for example in proximity to a main blood artery. Measuring the movement profile with the opto phone may therefore allow after calibration to extract an INR parameter representing a coagulation condition of blood.
  • a feature e.g., peak position and/or peak size
  • the pulse oxymeter is an optical sensor which is based on the fact that hemoglobin - the carrier of oxygen in the red blood cells - changes its absorption of visible light differently with varied oxygen levels. Hemoglobin which carries oxygen absorbs light at different wavelength than deoxygenated hemoglobin.
  • the oxymeter uses red and infra-red light emitter and a photo detector that receives the light that passes through the sensor site. In the experiments conducted by the inventors, the oxymeter served as the reference measurement device by attaching the oxymeter to the swine's tail. Oxygen level was recorded each 10 seconds. Laser beam was projected onto swine's chest, while the oxygen pumping machine was turned off and the swine stopped breathing which caused the oxygen values to drop down. Also, neuromuscular blocker was injected in order to prevent independent breathing.
  • Duration 150 Sec The following is the description of additional experiments of the invention demonstrating how the invention can be used for measuring various other parameters/conditions of a subject.
  • Figs. 28-32 refers to tests conducted by the inventors on rabbits, in order to determine a relationship between intra-ocular pressure (IOP) and parameters of the vibration profile of the subjects' eye in the time domain.
  • IOP intra-ocular pressure
  • ⁇ ( ⁇ ) can be used to estimate IOP.
  • the aim of the test was to show that the blood pressure in the blood vessels in the retina affects the movement of the sclera/iris in a way that is correlated to the IOP, i.e. the sclera/iris slightly pulsates due to the blood supply to the eye.
  • This movement although being very small, can be detected by the speckle-based measurement of the present invention, since the movement precision that our technique can allow is in the nanometric scale. It is important to emphasize that the measured movement is solely the pulse of the iris/sclera, and not the movements of the iris or the eye. The movements of the iris or the eye are undesirable, and can be we aim to filtered out by performing measurement over sufficiently short time scale.
  • rabbits had an infusion connected to their eye in order to control their IOP.
  • the experimental system was set up as the system of Fig. IB, where and the optically based monitoring system was positioned at range of about 50cm from the rabbit.
  • the system included a fast camera and a laser.
  • the readout of the camera was analyzed with Matlab software by a computer (control unit).
  • the experimental system monitored the secondary speckle patterns generated due to reflection from the rabbit's sclera, and tracked the trajectory of the movement of the speckle patterns.
  • the rabbits were anesthetized.
  • the source of coherent light was a harmonic of CW Nd:YAG laser which produced a beam having wavelength of 532nm to illuminate the sclera of the rabbit.
  • the reflections were analyzed using fast digital camera from "PixeLink". The obtained results were analyzed with Matlab software.
  • Fig. 28 there is depicted a graph illustrating the oscillation amplitude of a time-varying function describing the time varying position for the spatial correlation function's peak being indicative of the eye's vibration as a function of intraocular pressure (IOP), where the time varying-function was generated via the above- described system using a 2mW laser.
  • IOP intraocular pressure
  • the graph illustrates three different sets of measurements, each set being performed according to a different technique.
  • the uppermost curve 600 was obtained by sampling at rate of 100 frames/sec, while each measurement was taken separately and not in a continuous manner along the time axis.
  • the middle curve 602 corresponds to a measurement taken at sampling rate of 133 frames/sec in a continuous measuring manner.
  • the lowermost curve 604 was obtained using a continuous measuring but at sampling rate of 100 frames/sec.
  • the bars around each measurement designate the standard deviation that we had after averaging more than 20 measurements.
  • the current to the laser was 0.2 A which means illumination power of about 2mW.
  • Fig. 29 illustrates an example of the obtained readout in one of the performed experiments.
  • a time-varying function describing the time varying position of the peak of the spatial correlation function being indicative of the eye's pulsating motion was generated. Every 500 samples, the elevation of the infusion bag was changed. During these changes, high amplitude artifacts appear due to the change in the elevation of the infusion bag.
  • the oscillation amplitude of the time- varying function was measured and averaged for each set of 500 samples, in order to obtain an average amplitude corresponding to each elevation of the infusion bag (i.e. corresponding to a different IOP).
  • Fig. 31 there is depicted a graph illustrating the oscillation amplitude of time-varying function describing a time varying position of the peak of the 5 spatial correlation function (the time-varying function being indicative of the eye's vibration) as a function of intra-ocular pressure (IOP), where the IOP was measured via a Goldmann tonometer.
  • IOP intra-ocular pressure
  • both curves 600 and 604 have the same aspect but are scaled with respect to the global amplitude value. This is due to the fact that the lower the sampling rate, the lower is the amplitude of the speckle patterns.
  • the measurement error has standard deviation of about 15%.
  • the results depicted in Fig. 30 show a reduction of the standard deviation error until approximately 5%.
  • the reason for that improved performance is related to the timing of the measurement.
  • the results of Fig. 30 were obtained in the beginning stage of our experiment, while the results of Fig. 28 were obtained after large number of tests, which affected the structure and therefore also the IOP of the rabbit's eye.
  • the difference between the various curves of Fig. 28 and those of Fig. 30 arises either because the measurements were performed at different positions along the iris or because the measurements were performed on different eyes.
  • the standard deviation for each one of the curves in Figs. 28 and 30 is obtained for measurements performed in the same location for the same rabbit over the duration of the same experiment. This fact suggests that the standard deviation error may be independent of the measurement point.
  • Fig. 31 show a monotonic and a distinct relation between the absolute reference measurement of the IOP performed by Goldmann tonometer and the amplitude readout produced by the constructed optical device.
  • the Goldmann tonometer has a measurement error of about ImmHg.
  • the error of the present technique is about 0.775mmHg - considering standard deviation error of 5% and a typical IOP values in humans of 15.5mmHg in average. Therefore, the technique of the present invention provided both a lower measurement error (i.e. higher accuracy), as well as the advantage of remote and continuous monitoring capability.
  • the technique of the present invention can be used to determine blood pulse pressure.
  • a system similar to that of Fig. IB can be used to illuminate a region of a patient's skin adjacent to blood vessel(s) (e.g. the wrist).
  • Variations in the speckle pattern are detected and processed as described above to determine a correlation function and a time variation of a feature (e.g., peak position and/or peak size) of the correlation function.
  • the time variation of the spatial correlation function has a profile similar to that shown as shown in Fig. 6A, and the amplitude of the peaks is indicative of the blood flow in the measurement (illuminated) location.
  • the inventors have found that the amplitude of the main peak (parameter 1 of Fig. 6A) of the time varying spatial correlation function is in good correlation with the patient's blood pulse pressure, owing to the fact the time variation of the measured data (speckle pattern) corresponds to the blood flow (motion) within the measurement location.
  • Fig. 32 is a graph illustrating the change of a test subject's pulse amplitude over time, as compared to the test subject's pulse blood pressure.
  • the reference pulse pressure is shown by the curve denoted as curve ⁇ , and was obtained by subtracting diastolic pressure (curve 702) from systolic pressure (curve 700), both of which were measured using a manual sleeve-based reference measurement device.
  • the curve (denoted as M) illustrates the value of the pulse amplitude obtained using the proposed optical technique at same time as the above-mentioned reference measurements.
  • the time duration of the experiment was 350sec.
  • the sampling of the camera (PDA) was performed at 300Hz. It can be seen that a strong correlation exists between the reference curve ⁇ and the curve M obtained by the technique of the present invention.
  • the technique of the present invention can also be used to determine biomedical parameters of a ruminant.
  • Ruminant biomedical parameters monitoring such as monitoring of heart beating, pulse count, blood pulse pressure and breathing count can be very important in case of cattle as this information can be used to optimize the milking and the breeding timing of caws.
  • such monitoring is performed without contact which is appreciable when dealing with animals.
  • Applying the opto-phone technology and observing the surface of the skin of the caw, in positions that are close to a main blood artery may allow - after monitoring of the movement and after proper calibration - to extract the above mentioned biomedical parameters in real time and in a continuous manner.
  • the technique of the present invention can also be used to determine the temperature of a biological tissue.
  • a system similar to that of Fig. IB can be used to illuminate the biological tissue (e.g. a portion of skin of a body).
  • Variations in the speckle pattern are detected and processed as described above to determine a correlation function and a time variation of a feature (e.g., peak position and/or peak size) of the correlation function.
  • the temperature of a tissue is related to the temporal movement profile of the tissue. Therefore, by extracting this profile and after proper calibration it is possible to estimate the temperature of the inspected tissue.
  • the technique of the present invention can also be used to monitor the flow velocity and volume.
  • the flow velocity and volume may be correlated to temporal variations of the spectral content of the temporal pattern of the correlation peak extracted from a correlation function between successive defocused images of a speckle pattern generated at a surface of an organ in which the flow is monitored.
  • a correlation function between successive defocused images of a speckle pattern generated at a surface of an organ in which the flow is monitored.
  • the measurement of the opto phone provides sensing of the temporal movement profile of the inspected surface. It can be applied in plurality of wavelengths and in plurality of spatial positions. When plurality of wavelengths is applied, e.g. two, the measurements can be useful for application as oxymetry where the difference or the ratio of the temporal behavior at two wavelengths of absorption is inspected. In case of flow velocity the measurement can be done in one of two possible ways. In a first method, measurement of the temporal profile may be simultaneously performed at two (or more) spatial positions with a known distance between them. By correlating the temporal sequence of pulses extracted from the two spatial positions, the temporal relative shift between the two sets of pulses may be computed.
  • the measurement of the flow velocity can be done by doing only one measurement in a single spatial location.
  • the exact temporal profile of the pulsation is measured at high temporal resolution (with fast detector at sampling rate of e.g. GHz). Since the flow velocity affects the flow profile along the blood artery as explained above, the high precision extraction of the temporal pulsation profile can be related to the flow velocity. In all cases of measurement of the flow velocity and oxymetry etc, it is preferred to perform the measurement near principle blood artery where the pulsation affects are significantly more evident.
  • the inventors have conducted experiments aimed at measuring/detecting bond fractions.
  • laud speakers were placed close to a body portion, e.g. patient's hand.
  • the laud speakers generate acoustic signals, i.e. pressure waves, which cause vibrations to the patient's hand.
  • the movement of the bond having fractions is different from one without fractions.
  • the above-described opto phone (measurement unit) was used to inspect the movement of the skin and the bond (generate a sequence of the speckle patterns), and the control unit processes this data to identify whether there is a deviation from the calibrated value (which can be the second and the non broken hand.
  • the intensity of the speaker depends on the distance at which the speakers are positioned.
  • the speakers Positioning the speakers a few centimeters from the patient's hand (generally a body portion) and applying intensity of about 90dB provides that the speakers vibrate the hand, and if the bond has fractions it does not vibrate as a healthy hand does. This can be identified by doing proper calibration (i.e. mapping the hand before it was broken) or comparing the optical response between the two hands that are supposed to be substantially symmetrical.
  • the technique of the present invention for identifying/detection fractions in a bond first, the unbroken bone of the subject is inspected in means of vibration profile and frequencies domain. This measurement is used as a reference measurement.
  • the broken bone (or the one which is supposed to be broken) is inspected, while its vibration profile and frequencies are compared to the reference measurement in order to extract the differences and to define wherever the bone is broken or not.
  • the laser spot scans the hand and maps it point by point. This technique can be used as a replacement for or addition to a Roentgen image for observing fractions. This can be an indication for luck of calcium in bonds in elderly woman etc.
  • the present invention provides a novel, simple and effective technique for monitoring/measuring various conditions of a subject's body.

Abstract

L'invention concerne un système et un procédé destinés à une utilisation pour surveiller un ou plusieurs états du corps d'un sujet. Le système comprend une unité de commande qui comprend un port d'entrée pour la réception de données d'images, un utilitaire de mémoire et un utilitaire de traitement. Les données d'images sont indicatrices d'une séquence de motifs de taches générée par une partie du corps du sujet selon un certain schéma de temps d'échantillonnage. L'utilitaire de mémoire conserve un ou plusieurs modèles prédéterminés, le modèle comprenant des données indicatrices d'une relation entre un ou plusieurs paramètres mesurables et un ou plusieurs états du corps du sujet. L'utilitaire de traitement est configuré et opérable pour réaliser les étapes suivantes : le traitement des données d'images et la détermination d'une fonction de corrélation spatiale entre des motifs de taches successifs dans la séquence, et la détermination d'une fonction de corrélation spatiale variant dans le temps sous la forme d'une fonction variant dans le temps d'au moins une caractéristique de la fonction de corrélation, la fonction de corrélation spatiale variant dans le temps étant indicatrice d'un changement du motif de taches avec le temps; la sélection d'au moins un paramètre de la fonction de corrélation spatiale variant dans le temps, et l'application audit ou auxdits paramètres un ou plusieurs des modèles afin de déterminer un ou plusieurs états correspondants du corps; et la génération de données de sortie indicatrices dudit ou desdits états du corps.
PCT/IL2013/050658 2011-01-28 2013-08-01 Procédé et système pour la surveillance non invasive de paramètres biologiques ou biochimiques d'un individu WO2014020611A1 (fr)

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EP13753907.8A EP2879568A1 (fr) 2012-08-01 2013-08-01 Procédé et système pour la surveillance non invasive de paramètres biologiques ou biochimiques d'un individu
CN201380041088.5A CN104736042B (zh) 2012-08-01 2013-08-01 用于非侵入地监测个体的生物参数或生化参数的方法和系统
JP2015524904A JP6645828B2 (ja) 2012-08-01 2013-08-01 個体の生物学的又は生化学的パラメータを非侵襲的にモニタする方法及びシステム
CA2879255A CA2879255C (fr) 2012-08-01 2013-08-01 Procede et systeme pour la surveillance non invasive de parametres biologiques ou biochimiques d'un individu
US14/168,730 US9636041B2 (en) 2011-01-28 2014-01-30 Method and system for non-invasively monitoring biological or biochemical parameters of individual
IL236742A IL236742B (en) 2012-08-01 2015-01-15 Method and system for non-intrusive monitoring of glucose-related parameters of an individual
HK15111056.1A HK1210001A1 (en) 2012-08-01 2015-11-10 Method and system for non-invasively monitoring biological or biochemical parameters of individual
US15/483,828 US10398314B2 (en) 2012-08-01 2017-04-10 Method and system for non-invasively monitoring biological or biochemical parameters of individual

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US201261678131P 2012-08-01 2012-08-01
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US13/564,381 US9668672B2 (en) 2011-01-28 2012-08-01 Method and system for non-invasively monitoring biological or biochemical parameters of individual
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US10398314B2 (en) 2019-09-03
IL236742B (en) 2020-06-30
CN104736042B (zh) 2017-09-12
JP2020000883A (ja) 2020-01-09
EP2879568A1 (fr) 2015-06-10
CA2879255C (fr) 2020-11-10
US20170209047A1 (en) 2017-07-27
CN104736042A (zh) 2015-06-24
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IL236742A0 (en) 2015-02-26
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